The two objectives of this application are to support my training as a physician-scientist and to establish the importance of RET tyrosine kinase and its coreceptors and ligands in spermatogenesis. This award will facilitate my transition into an independent investigator by providing molecular laboratory training under the mentorship of Dr. Jeffrey Milbrandt, Professor of Pathology and Immunology and Internal Medicine at Washington University School of Medicine. Dr. Milbrandt is ideally suited to be my mentor for several reasons. His laboratory has significant experience in studying RET, its coreceptors and ligands and has all the available resources, including mouse models, antibodies, probes, etc., already in place to facilitate successful completion of the proposed application. He has previously served as research mentor to eight, K08 recipients in the past 10 years. I will receive continuity of training, as I have previously worked in his laboratory for three years. A didactic program in molecular biology will complement the intellectual environment provided by Dr. Milbrandt's laboratory, the Siteman Cancer Center Developmental Biology Research Meetings, and the Division of Urologic Surgery Research Conferences. The importance of RET, its coreceptors and ligands in spermatogenesis is evidenced by testis expression studies, abnormalities in spermatogenesis of mouse models with mutations of the RET receptor, and loss of RET protein expression in human cases of maturation arrest and male infertility. Maturation arrest is a cause of male-factor infertility due to failure of existing testicular germ cells to mature. Presently, there is no therapy for these patients, and the only potential option for these couples for their own biological children is in vitro fertilization with intracytoplasmic sperm injection. Identification of the component(s) responsible for continued sperm maturation in these men is first necessary in order to target future therapies to facilitate sperm maturation in vivo. The specific aims of this proposal will explore the role of RET in spermatogenesis to determine if signaling through RET is important for germ cell survival, proliferation, and/or maturation. This will be accomplished by studying the disturbed spermatogenesis identified in a mouse model carrying a mutation of the RET receptor. The translation to human disease will be achieved by studying RET expression in male infertility cases of maturation arrest.